Aminophylline

Aminophylline may be found in some form under the following brand names:

• Mudrane

• Mudrane GG

• Mudrane GG-2

• Phyllocontin

• Truphylline

• Phosphodiesterase Enzyme Inhibitor, Nonselective

Theophylline has two distinct actions; smooth muscle relaxation (ie, bronchodilation) and suppression of the response of the airways to stimuli (ie, non-bronchodilator prophylactic effects). Bronchodilation is mediated by inhibition of two isoenzymes, phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilation effects are mediated through other molecular mechanisms. Theophylline increases the force of contraction of diaphragmatic muscles through enhancement of calcium uptake through adenosine-mediated channels.

Distribution

Theophylline: ~0.45 L/kg based on ideal body weight; distributes poorly into body fat; Vd may increase in premature neonates, hepatic cirrhosis, acidemia (uncorrected), elderly, and third trimester of pregnancy.

Metabolism

Theophylline: Hepatic via demethylation (CYP 1A2) and hydroxylation (CYP 2E1 and 3A4); forms active metabolites (caffeine and 3-methylxanthine).

Excretion

Theophylline: Urine (~50% as unchanged drug [Neonates]; ~10% as unchanged drug [Infants >3 months, Adolescents, and Adults])

Time to Peak

Serum: Theophylline: Within 30 minutes

Half-Life Elimination

Theophylline: Highly variable and dependent upon age, hepatic function, cardiac function, lung disease, and smoking history

Premature infants, postnatal age 3 to 15 days: 30 hours (range: 17 to 43 hours)

Premature infants, postnatal age 25 to 57 days: 20 hours (range: 9.4 to 30.6 hours)

Term infants, postnatal age 1 to 2 days: 25.7 hours (range: 25 to 26.5 hours)

Term infants, postnatal age 3 to 30 weeks: 11 hours (range: 6 to 29 hours)

Children 1 to 4 years: 3.4 hours (range: 1.2 to 5.6 hours)

Children and Adolescents 6 to 17 years: 3.7 hours (range: 1.5 to 5.9 hours)

Adults ≥18 years to ≤60 years (asthma, nonsmoking, otherwise healthy): 8.7 hours (range: 6.1 to 12.8 hours)

Elderly >60 years (nonsmoking, healthy): 9.8 hours (range: 1.6 to 18 hours)

Protein Binding

Theophylline: ~40%, primarily to albumin; decreased in neonates (due to a greater percentage of fetal albumin), hepatic cirrhosis, acidemia (uncorrected), elderly, third trimester of pregnancy.

Clearance is decreased in infants <3 months with decreased renal function.

Reversible airflow obstruction: Treatment of acute exacerbations of symptoms and reversible airflow obstruction due to asthma or other chronic lung diseases (eg, emphysema, chronic bronchitis) as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids.

Guideline recommendations:

Asthma: The 2007 National Heart, Lung, and Blood Institute Asthma Guidelines and the 2016 Global Initiative for Asthma Guidelines (GINA) recommend against aminophylline for the treatment of asthma exacerbations because of poor efficacy and safety concerns (GINA 2016; NAEPP 2007).

COPD: The 2017 Global Initiative for Chronic Obstructive Lung Disease Guidelines recommends against aminophylline for the treatment of COPD exacerbations because of significant adverse effects (GOLD 2017).

Note: All dosages expressed as aminophylline; use ideal body weight (theophylline distributes poorly into body fat) to calculate dose; individualize dose based on steady-state serum concentrations. Theophylline dose is ~79% of aminophylline dose. The treatment of asthma exacerbations with aminophylline is not supported or recommended by current clinical practice guidelines (GINA 2016; NAEPP 2007). The treatment of acute COPD exacerbations with aminophylline is not recommended by current clinical practice guidelines (Global Initiative for COPD Guidelines 2017).

Reversible airflow obstruction, acute symptoms:

Loading dose: IV: Refer to adult dosing.

Maintenance dose: IV: Note: Dosing presented is to achieve a target theophylline concentration of 10 mcg/mL unless otherwise noted. Lower initial doses may be required in patients with reduced theophylline clearance. Dosage should be adjusted according to serum level measurements.

Infants 4 to 6 weeks: 1.9 mg/kg/dose every 12 hours (to achieve a target concentration of 7.5 mcg/mL for neonatal apnea).

Infants 6 to 52 weeks: Dose (mg/kg/hour) = [(0.008 x age in weeks) + 0.21] divided by 0.79

Children 1 to <9 years: 1.01 mg/kg/hour

Children 9 to <12 years: 0.89 mg/kg/hour

Adolescents 12 to <16 years (cigarette or marijuana smokers): 0.89 mg/kg/hour

Adolescents 12 to <16 years (nonsmokers): 0.63 mg/kg/hour; maximum dose: 1,139 mg/day unless serum levels indicate need for larger dose

Adolescents ≥16 years: Refer to adult dosing.

Cardiac decompensation, cor pulmonale, sepsis with multiorgan failure, and shock: Refer to adult dosing.

Dosage adjustment based on serum theophylline concentrations: Note: Recheck serum theophylline concentration 12 hours after dosage adjustment.

<9.9 mcg/mL: If dosage is tolerated, but symptoms are not controlled, increase infusion rate ~25%.

10 to 14.9 mcg/mL: Maintain infusion rate if dosage is tolerated and symptoms controlled. Recheck serum concentrations at 24-hour intervals. If symptoms are not controlled and dosage is tolerated, consider adding additional medications to treatment regimen.

15 to 19.9 mcg/mL: Consider 10% dose reduction in infusion rate to improve safety margin even if dose is tolerated.

20 to 24.9 mcg/mL: Decrease infusion rate by 25% even if no adverse effects present.

25 to 30 mcg/mL: Stop infusion for 12 hours and decrease subsequent infusion rate at least 25%. If symptomatic, stop infusion and consider whether overdose treatment is indicated.

>30 mcg/mL: Stop infusion and treat overdose; if resumed, decrease subsequent infusion rate at least 50%.

Plasma glucose, uric acid, free fatty acids, total cholesterol, HDL, HDL/LDL ratio, and urinary free cortisol excretion may be increased by theophylline. Theophylline may decrease triiodothyronine.

Concerns related to adverse effects:

• Extravasation: Vesicant; ensure proper catheter or needle position prior to and during infusion. Avoid extravasation.

• Theophylline toxicity: Severe and potentially fatal theophylline toxicity may occur if reduced theophylline clearance occurs. Theophylline clearance may be decreased in patients with acute pulmonary edema, heart failure, cor pulmonale, fever (≥102°F for ≥24 hours or lesser temperature elevations for longer periods), hepatic disease, acute hepatitis, cirrhosis, hypothyroidism, sepsis with multiorgan failure, shock, neonates (term and premature), infants <3 months of age with decreased renal function, infants <1 year, elderly >60 years, and patients following cessation of smoking. Consider benefits versus risks and the need for more intensive monitoring in these patients; reduced infusion rate required. If a patient develops signs and symptoms of theophylline toxicity (eg, nausea or persistent, repetitive vomiting), a serum theophylline level should be measured immediately and subsequent doses withheld.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiac arrhythmias (excluding bradyarrhythmias); use may exacerbate arrhythmias.

• Cystic fibrosis: Use with caution in patients with cystic fibrosis; increased theophylline clearance may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment (eg, cirrhosis, acute hepatitis, cholestasis); risk of severe and potentially fatal theophylline toxicity is increased. Theophylline clearance is decreased ≥50% in these patients. Dose reduction and frequent monitoring of serum theophylline concentrations are required.

• Hyperthyroidism: Use with caution in patients with hyperthyroidism; increased theophylline clearance may occur.

• Peptic ulcer disease: Use with caution in patients with active peptic ulcer disease; use may exacerbate peptic ulcer.

• Seizure disorder: Use with caution in patients with seizure disorders; use may exacerbate seizure disorder.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use extreme caution in the elderly; these patients are at greater risk of serious theophylline toxicity.

• Pediatric: Select dose with caution and with frequent monitoring of concentrations (especially <1 year); rate of clearance is highly variable in these patients.

Other warnings/precautions:

• Appropriate use: Do not increase dose in response to acute exacerbation of symptoms unless steady state serum theophylline concentration is <10 mcg/mL. As the rate of theophylline clearance may be dose-dependent, an increase in dose based upon a subtherapeutic serum concentration measurement should be limited to ~25% increase of the previous infusion rate or daily dose.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience agitation, insomnia, or polyuria. Have patient report immediately to prescriber signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), muscle pain, muscle weakness, tachycardia, abnormal heartbeat, fast breathing, severe dizziness, passing out, severe anxiety, nausea, vomiting, severe diarrhea, abdominal pain, severe headache, confusion, seizures, or tremors (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Substance Name

Aminophylline

CAS Registry Number

317-34-0

Drug Class

Anti-Asthmatic Agents

Bronchodilators